Hepatitis C virus (HCV) is a major public health problem worldwide. Only 15-30% of infected individuals clear the virus spontaneously, while the majority develops chronic infection that causes liver complications. The only approved therapy for HCV is interferon alpha (IFN-α) based. This therapy has a 50-80% success rate depending on the infecting virus genotype and the timing of initiation of therapy. Factors governing the response to therapy are not well defined. Previous studies have suggested a role for the host immune response in the success of therapy. However, these results were controversial.
We hypothesized that host immunity has an effective role in the success of IFN-α therapy when initiated early during the acute phase of HCV infection, while late initiation during the chronic phase minimizes this role. The main objective of this thesis was to dissect the immunological factors governing the differential response to IFN-α therapy, and to determine if the contribution of the immune response to success of therapy might be influenced by the period of infection.
Our results demonstrate restoration of efficient HCV-specific immune responses when therapy is initiated early during the acute phase. This is demonstrated by the rescue of functional HCV-specific T cells similar to those observed in spontaneously resolved individuals, suggesting that they may play an active role in response to therapy. However, such responses were not restored following late therapy suggesting irreversible damage to the host’s defence system with chronicity. These findings have important implications in understanding the mechanisms underlying response to current treatments and development of novel therapies.